Approximately 2,500,000 people were infected with human immunodeficiency virus (HIV) in 2007, underscoring the urgency of developing an effective prophylactic vaccine. The first vaccine designed to elicit CD8+ T cell responses and advance into late-stage clinical trials failed. There is thus considerable debate whether CD8+ T cells alone can protect from acquisition of HIV or reduce the severity of HIV infection. We hypothesize that CD8+ T cells directed against a single viral target, or epitope, can blunt early viral replication if present in sufficient numbers at the time of infection. In this proposal we will test this hypothesis by identifying CD8+ T cells that combat SIV and characterizing their ability to suppress viral replication in vitro. We have identified a population of macaques susceptible to simian immunodeficiency virus (SIV), the genetic cousin of HIV that tolerates infusions of CD8+ T cells derived from other macaques. If we successfully identify a suppressive CD8+ T cell specificity in the first two years of this proposal, then we will transfer massive numbers of these cells into SIV-naive macaques immediately before SIV challenge. If successful, these experiments will prove that CD8+ T cells alone can protect against SIV and support continued development of CD8+ T cell vaccines.